WO2012058203A1 - Dérivés hétérocycliques de diazéniumdiolate - Google Patents

Dérivés hétérocycliques de diazéniumdiolate Download PDF

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Publication number
WO2012058203A1
WO2012058203A1 PCT/US2011/057641 US2011057641W WO2012058203A1 WO 2012058203 A1 WO2012058203 A1 WO 2012058203A1 US 2011057641 W US2011057641 W US 2011057641W WO 2012058203 A1 WO2012058203 A1 WO 2012058203A1
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WIPO (PCT)
Prior art keywords
ium
diazen
diolate
butyl
methylamino
Prior art date
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PCT/US2011/057641
Other languages
English (en)
Inventor
Amjad Ali
Michael Man-Chu Lo
Robert K. Baker
Zhiqiang Guo
Brent Whitehead
Timothy J. Henderson
Edward Metzger
Lin Yan
Shrenik K. Shah
James Dellureficio
Jun Wang
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Merck Sharp & Dohme Corp.
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Application filed by Merck Sharp & Dohme Corp. filed Critical Merck Sharp & Dohme Corp.
Priority to RU2013124814/04A priority Critical patent/RU2013124814A/ru
Priority to US13/881,929 priority patent/US9108920B2/en
Priority to KR1020137010699A priority patent/KR20130143042A/ko
Priority to CN2011800633795A priority patent/CN103347385A/zh
Priority to CA2814752A priority patent/CA2814752A1/fr
Priority to BR112013009389A priority patent/BR112013009389A2/pt
Priority to MX2013004739A priority patent/MX2013004739A/es
Priority to AU2011320595A priority patent/AU2011320595A1/en
Priority to JP2013536718A priority patent/JP2013540817A/ja
Priority to EP11836944.6A priority patent/EP2632255B1/fr
Publication of WO2012058203A1 publication Critical patent/WO2012058203A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P9/12—Antihypertensives
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    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • WO09103875 describes diazeniumdiolate dihydro indole derivatives of a specified formula for treating hypertension and cardiovascular disease.
  • WO07144512 describes diazeniumdiolate tetrazole-biphenyl derivatives of a specified formula for treating hypertension and cardiovascular disease.
  • US 2005137191 describes nitrate ester compounds, e.g., 1 » 2- dichloro-4-(2-methyl-butyldisulfanyl)-benzene s useful for preventing or mitigating tissue and/or cellular damage associated with aging, septic shock, ulcers, gastritis, ulcerative colitis and Crohn's disease.
  • US 2005065194 describes use of an endothelial gene differentiation receptor modulator such as l-(2-emoxyphenyl)-3-(hydroxyphenylamino)-pyrrolidine-2,5-dione, to modulate receptor-mediated biological activity such as cell proliferation stimulated by lysophosphatidic acid leading to ovarian cancer and other forms of cancer, and to treat conditions such as cancer, cardiovascular disease, ischemia, and atherosclerosis.
  • WO 9746521 describes aliphatic nitrate esters useful for treating neurological conditions, especially Parkinson's, Alzheimer's and Huntington's disease.
  • the present invention relates to novel diazeniumdiolate heterocyclic derivatives, useful as antihypertensive agents.
  • the present invention includes diazeniumdiolate heterocyclic derivatives, including various pharmaceutically acceptable salts and hydrates of these forms, and
  • the invention also includes a method for treating hypertension, Pulmonary
  • PHY Arterial Hypertension
  • congestive heart failure conditions resulting from excessive water retention, cardiovascular disease, diabetes, oxidative stress, endothelial dysfunction, cirrhosis, pre-eclampsia, osteoporosis or nephropathy, comprising administering a compounds of the invention to a patient having such a condition, or being at risk to having such condition.
  • the invention is a compound of formula I:
  • R 3 and R 4 are independently
  • the compound is of formula la, which is In another embodiment, the compound is of formula lb, which is
  • R? is
  • R? is -CeHs
  • R7 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • I S and R ⁇ > are independently hydrogen or deuterium.
  • R3 is -CD2C1.5al.iyl, -C(CH3)3, -CH2CH3, or
  • R4 is -CD2Ci-.5al.cyl, -CH3, -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3, -CH2CH2-phenyl, -CH2-phenyl, -CD2CH3, -CH2CH2OH, -CH2C(O)OH, -CH2CH20C(O)CH3.
  • ⁇ CH2CH CH2.
  • the compound is of of formula li:
  • X is O or NR7
  • the compound is of formula iai, which is
  • the compound is of formula Ibi, which is
  • Rl is hydrogen, -C(0)OH, or ⁇ C(0)OCH3.
  • R2 is hydrogen
  • R? is
  • R7 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R7 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R7 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R7 is ⁇ -C 6 Hn or -CsHg.
  • R5 is hydrogen, -CH3, -C(0)OCH3, -C(0)OH, or phenyl.
  • R0 is hydrogen or -CH3.
  • R3 is ⁇ C(CH3)3 or -CH2CH3.
  • R4 is -CH3. -CH2CH3, -CH2CH2CH3, -CH2CH2CH2CH3 , -CH 2 CH2-phenyl, -CD2CH3, -CH2CH20H, or -CH2CH20C(0)CH3.
  • Compounds of the invention can be used to treat hypertension, treat angina, improve insulin sensitivity, and provide renal protection.
  • the compounds can be used alone or in combination (e.g., separate but co-administered, or administered in a fixed dose) with other antihypertensives such as, for example, angiotensin II receptor blockers, diuretics, ACE inhibitors, ⁇ -blockers, and calcium channel blockers.
  • salts include non-toxic salts such as those derived from inorganic acids, e.g. hydrochloric, hydrobromoic, sulfuric, sulfamic, phosphoric, nitric and the like, or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.
  • acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, carbonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, lactobionate, laurylsulfate, malate, maleate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, pamoate, pe
  • Additional specific anionic salts include ascorbate, gluceptate, glutamate, glucoronate, besylate, caprylate, isetionate, gentisate, malonate, napasylate, edfisylate, pamoate, xinafoate, and napadisylate.
  • Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as argi ine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
  • Additional specific cationic salts include tromethamine, benzathine, benethamine, diethylammonium, epolamine, hydrabamine.
  • stereoisomer includes both enantiomers and mixtures of enantioniers, such as the specific 50:50 mixture referred to as the racemic mixture.
  • the compounds of the present invention may have multiple chiral centers, providing for multiple stereoisomers.
  • This invention includes all of the stereoisomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, all possible stereoisomers are included.
  • the structure marking "*" indicates the location of a carbon atom that is a chiral center. When bonds to a chiral carbon are depicted as straight lines, it is understood that both (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are represented.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of Formula I.
  • different isotopic forms of hydrogen (H) include protium ( ⁇ ) and deuterium (3 ⁇ 4 ⁇ ).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Commonly used abbreviations for alkyl groups are used throughout the specification, e.g. methyl may be represented by conventional abbreviations including "Me” or CH 3 or a symbol that is an extended bond as the terminal group, e.g. ⁇ , ethyl may be represented by "Et” or CH2CH3, propyl may be represented by "Pr” or CH 2 CH 2 CH 3 , butyl may be represented by "Bu” or CH 2 CH 2 CH 2 C3 ⁇ 4 , etc.
  • w C alkyl (or "C1-C4 alkyl") for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms.
  • Cl -4 alkyl includes n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. If no number is specified, 1-4 carbon atoms are intended for linear or branched alkyl groups.
  • alkylene refers to any divalent linear or branched chain aliphatic hydrocarbon radical having a number of carbon atoms in the specified range.
  • -C1-C6 alkylene- refers to any of the C] to C$ linear or branched alkylenes
  • -C1-C4 alkylene- refers to any of the C] to C4 linear or branched alkylenes.
  • Another sub-class of interest is an alkylene selected from the group consisting of -CH2-,
  • Alkyl groups and alkylene groups may be unsubstituted, or substituted with 1 to 3 substituents on any one or more carbon atoms, with halogen, C1-C20 alkyl, CF3, NH2, -NH(Ci - C6 alkyl), -N(Ci-C6 alkyl)2, NO2, oxo, CN, N3, -OH, -OC(0)Ci-Ce alkyl, -0(Ci-C6 alkyl), C3-C10 cycloalkyl, C 2 -C aikenyl, C 2 -C 6 alkynyl, (Ci -C 6 alkyI)S(O)0-2-, HS(O)0-2-, (Ci-C 6 alky])S(O)0-2(Cl-C 6 alkyl)-, HS(O) 0 -2(Cl-C 6 alkyl)-, (C 0 -C 6 alkyl)C(0)NH
  • aryl alone or in combination, relates to a phenyl, naphthyl or indanyl group, preferably a phenyl group.
  • the abbreviation "Ph” represents phenyl.
  • carbocycle refers to a C3 to C& monocyclic saturated or unsaturated ring.
  • the carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound.
  • Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.
  • heteroaryl refers to an unsaturated ring having 5 or 6 atom ring members including 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, e.g., 5-membered rings containing one nitrogen (pyrrole), one oxygen (pyran) or one sulfur (thiophene) atom, 5-membered rings containing one nitrogen and one sulfur (thiazole) atom, 5-membered rings containing one nitrogen and one oxygen (oxazole or isoxazole) atom, 5- membered rings containing two nitrogen (imidazole or pyrazole) atoms, five-membered aromatic rings containing three nitrogen atoms, five-membered aromatic rings containing one oxygen, one nitrogen or one sulfur atom, five-membered aromatic rings containing two heteroatoms independently selected from oxygen, nitrogen and sulfur, 6-membered rings containing one nitrogen (pyridine), or one oxygen (furan) atom, 6-membered rings containing two nitrogen (pyrazin
  • (triazine) atoms a tetrazolyl ring; a thiazinyl ring; or coumarinyl.
  • ring systems are furanyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, indolyl, imidazolyl, triazinyl, thiazolyl, isothiazolyl, pyridazinyl, pyrazolyl, oxazolyl, and isoxazolyl.
  • heterocycle and “heterocyclic” refer to a saturated ring having a specified number of atom members and a specified number of heteroatoms, in which the entire ring system (whether mono- or poly-cyclic) is saturated, e.g., a 4- to 8-membered saturated monocyclic ring or a stable 7- to 12-membered bicyclic ring system which consists of carbon atoms and one or more heteroatoms selected from N, O and S, a 5- or 6- membered heterocyclic ring having 1 or 2 heteroatoms which are N, O or S, etc.
  • Representative examples include piperidznyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazo!idinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl),
  • Aryl groups and carbocycles may be unsubstituted, or substituted with 1, 2, or 3 substituents on any one or more available carbon atoms, with halogen, C1-C2O alkyl, CF3, NH 2> -NH(Ci-C6 alkyl), -N(Ci-C6 alkyl)2, NO2, oxo, CN, N3, -OH, -0(Ci-C6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C alkynyl, HS(O)0-2-, (Cl-C 6 alkyl)S(O)0-2-, (Cl-C 6 alkyl)S(O) 0 -2(Cl -C 6 alkyl)-, HS(O)0 ⁇ 2(Cl-C 6 alkyl)-, (Ci-C 6 alkyl)S(O) 0 -2, (C1-C6 alkyl)C(0)
  • Heteroaryl groups and heterocycles may be unsubstituted, or substituted with 1 , 2, or 3 substituents on any one or more available carbon atoms, with halogen, C1- 20 alkyl, CF3, NH 2 , -NH(Cl -C ⁇ 5 alkyl), -N(Ci -C6 alkyl) 2 , N0 2 , oxo, CN, N3, -OH, -0(Ci-C 6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (Q-C 6 aJkyl)S(O)0- 2 -, HS(O)0-2-, (Cl-C 6 alkyl)S(O) 0 -2(Cl-C 6 alkyl)-, HS(O) 0 ⁇ 2(Cl-C 6 alkyl)-, (C ⁇ -C 6 alkyl)S(O)
  • Substituted heterocyclic rings include cyclic ureas, such as imidazolidin-2-one and tetrahydropyrimidin -2(lH)-one, which rings contain three sequential atoms that are nitrogen, carbon and niotrogen, wherein the carbon atom is substituted with an oxo substituent.
  • the compounds of the invention are useful for treating hypertension, Pulmonary Arterial Hypertension, congestive heart failure, angina, conditions resulting from excessive water retention, cardiovascular diseases, diabetes, oxidative stress, endothelial dysfunction, cirrhosis, pre-eclampsia, osteoporosis, or nephropathy, comprising administering a compounds of the invention to a patient having such a condition, or being at risk to having such condition
  • the invention also relates to the use of compounds of the invention for the preparation of a medicament for the treatment and/or prophylaxis of the above-mentioned diseases.
  • angiotensin II receptor antagonists e.g., losartan, valsartan, candesartan, irbesartan, olmesartan
  • angiotensin converting enzyme inhibitors e.g, alacepril, benazepril, captoprii, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril), neutral endopeptidase inhibitors (e.g., thiorphan and
  • phosphoramidon aldosterone antagonists
  • renin inhibitors e.g. urea derivatives of di- and tri- peptides (See U.S. Pat. No. 5,116,835), amino acids and derivatives (U.S. Patents 5,095,119 and 5, 104,869), amino acid chains linked by non-peptidic bonds (U.S. Patent 5,1 14,937), di- and tri- peptide derivatives (U.S. Patent 5,106,835), peptidyl amino diols (U.S. Patents 5,063,208 and 4,845,079) and peptidyl beta-aminoacyl aminodiol carbamates (U.S.
  • Patent 5,089,471) also, a variety of other peptide analogs as disclosed in the following U.S. Patents 5,071,837; 5,064,965; 5,063,207; 5,036,054; 5,036,053; 5,034,512 and 4,894,437, and small molecule renin inhibitors (including diol sulfonamides and sulfmyls (U.S. Patent 5,098,924), N-morpholino derivatives (U.S. Patent 5,055,466), N-heterocyclic alcohols (U.S. Patent 4,885,292) and pyrolimidazolones (U.S. Patent 5,075,451); also, pepstatin derivatives (U.S.
  • Patent 4,980,283) and fiuoro- and chloro-derivatives of statone-containing peptides (U.S. Patent 5,066,643), enalkrein, RO 42- 5892, A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren ⁇ S ⁇ S ⁇ S ⁇ S) ⁇ - carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-rriethoxy-3-(3- methoxypropoxy)phenyl]-octanamid hemifumarate) SPP600, SPP630 and SPP635), endothelin receptors antagonists, vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, verastrial, diltiazem, gallopamil, niludipine, nimodipins,
  • lipid lowering agents e.g., simvastatin, lovastatin, ezetamibe, atorvastatin, pravastatin
  • metabolic altering agents including insulin sensitizing agents and related compounds including (i) PPAR.gamma. agonists, such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, balaglitazone, and the like) and other PPAR ligands, including PPAR.aipha. .
  • gamma dual agonists, such as RP-297, muraglitazar, naveglitazar, Galida, tesaglitazar, TA -559, PPAR.aipha. agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), and selective PPAR.gamma. modulators (SPPAR.gamma.
  • the dosage regimen utilizing the compound of the invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition,
  • Oral dosages of the compounds of the invention when used for the indicated effects, will range between about 0.0125 mg per kg of body weight per day (mg/kg/day) to about 7,5 mg kg/day, preferably 0.0125 mg kg day to 3,75 mg kg/day, and more preferably 0.3125 mg/kg/day to 1.875 mg/kg/day.
  • an 80 kg patient would receive between about 1 mg/day and 600 mg/day, preferably 1 mg/day to 300 mg/day, more preferably 25 mg/day to 150 v mg/day, and more preferably 5 mg/day to 100 mg/day.
  • a suitably prepared medicament for once a day administration would thus contain between 1 mg and 600 mg, preferably between 1 mg and 300 mg, and more preferably between 25 mg and 300 mg, e.g., 25 mg, 50 mg, 100 mg, 150, 200, 250 and 300 mg ? .
  • the compound of the invention may be administered in divided doses of two, three, or four times daily.
  • a suitably prepared medicament would contain between 0.5 mg and 300 mg, preferably between 0.5 mg and 150 mg, more preferably between 12.5 mg and 150 mg, e.g., 12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg and 150 mg.
  • the compounds of the invention can be administered in such oral forms as tablets, capsules and granules.
  • the compounds of the invention are typically administered as active ingredients in admixture with suitable pharmaceutical binders as described below.
  • % w/w expresses the weight percent of the indicated composition constituent compared to the total composition.
  • suitable fillers used in these dosage forms include microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, lactose, mannitol, and starch, preferably microcrystalline cellulose, dicalcium phosphate, lactose or mixtures thereof.
  • Suitable binders include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, and polyvinyl pyrrolidone.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, sodium stearyl fumarate, stearic acid and the like, preferably magnesium stearate.
  • Suitable coating compositions include aqueous dispersion or organic solution of insoluble polymers such as ethyl cellulose, cellulose aetate, cellulose acetate butyr te and aery late copolymers commercially known as Eudragit®.
  • Plasticizers include triethyl citrate, dibutyl sebacate, dibutyl phthalate, triacetin and castor oil.
  • Antitacking agents include talc, kaolin, colloidal silica or mixtures thereof.
  • Scheme 1 delineates a method to prepare 0 2 -alkylated diazeniumdiolates of the general structure 1-4 in this invention.
  • Aminoalcohols of the general structure 1-1 can be prepared from reduction of the corresponding ketone or hydroboration/oxidation of the corresponding olefin.
  • the amino group of 1-1 can react with the proper electrophile, such as acid chloride, acid anhydride, chloroformate, sulfonyl chloride, isocyanate, cyanogen bromide, or alkyl halide in the presence of a base such as N,N-diisopropylethylamine, triethylamine, N- methylmorpholine, pyridine, or lutidine in an appropriate solvent such as dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane, toluene, N,N- dimethylforrnamide, or N-methylpyrrolidinone, to afford the functionalized aminoalcohol 1-2.
  • a base such as N,N-diisopropylethylamine, triethylamine, N- methylmorpholine, pyridine, or lutidine in an appropriate solvent
  • R 7 when R 7 is an aromatic ring / heteroaromatic ring, it can be synthesized by coupling (hetero)aryl halides to the aminoalcohol 1-1 through the use of a catalytic amount of palladium complex, such as palladium(ii) acetate, tris(dibenzylideneacetone) dipalladium(O), with an appropriate ligand, such as tri-/er -butylphosphine s l,l '-bis(dicyclohexylphosphino) ferrocene, (2 ⁇ biphenyl)di ⁇ fer/-butylphosphine 5 2 ⁇ dicycIohexylphosphino-2 '-(N,N ⁇
  • palladium complex such as palladium(ii) acetate, tris(dibenzylideneacetone) dipalladium(O)
  • an appropriate ligand such as tri-/er -butylphosphine
  • dimethylamino)biphenyl or a preformed palladium-ligand complex, such as chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl- 1 , 1 '-biphenyl)[2-(2-aminoethyl)phenyl)]
  • the desired aminoalcohol 1-2 can be obtained by heating aminoalcohol 1-1 and the corresponding aromatic / heteroaromatic compound with an appropriate leaving group in a solvent of high boiling point, such as dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidinone, or l ,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone in the presence of a base such as triethylamine, N,N-diisopropylethylamine, or potassium carbonate.
  • a solvent of high boiling point such as dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidinone, or l ,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone
  • a base such as triethylamine, N,N-diisopropylethylamine, or potassium carbonate.
  • the functionalized aminoalcohol 1-2 can be activated for displacement at an appropriate temperature such as room temperature with a suitable reagent such as methanesulfonic anhydride, benzenesulfonyl chloride, 4-(trifluoromethyi)phenylsulfonyl chloride in the presence or absence of a base such as N,N-diisopropylethylamine 5 triethylamine, N-methylmorpholine, pyridine, or lutidine in an appropriate solvent such as dichloromethane, dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane, toluene, N 5J V-dimethylformamide, or N-methylpyrrolidinone.
  • the resultant sulfonate 1-3 can be displaced by the appropriate sodium diazeniumdiolate salt at an appropriate temperature such as room temperature in an appropriate solvent such as
  • dichloromethane dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane, toluene, 7V,N-dimethylformamide, or N-methylpyrrolidinone.
  • the stereochemistry at the sulfonate carbon is typically inverted as a result of the displacement.
  • X 1 -R 7 acid chloride, acid anhydride, chioroformate, sutfonyl chloride, isocyanate,
  • R 8 straight or branched C 1-6 alkyi, unsubstituted phenyl, or phenyl substituted with Chalky!
  • Scheme 2 describes a method to prepare O -alkylated diazeniumdiolates of the general structure 2-5 in this invention.
  • the N ⁇ fer -butoxycarbonyI protected aminoaicohol 2-1 can be activated for displacement at an appropriate temperature such as room temperature with a suitable reagent such as methanesulfonic anhydride, benzenesulfonyl chloride, 4-
  • the stereochemistry at the sulfonate carbon is typically inverted as a result of the displacement.
  • the N-ierr-butoxycarbonyl derivative 2-3 can be deprotected, typically with an appropriate acid such as trifluoroacetic acid, hydrochloric acid, phosphoric acid, or any other method described in Wuts, P. G. M.; Greene, T. W.
  • X 1 -R 7 acid chloride, acid anhydride, chloroformate, sulfonyl chloride, isocyanate,
  • R 8 straight or branched chain Chalky!, unsubstituted phenyl, or phenyl substituted with C 1-6 a!kyl
  • Step A fert-butyl (3S)-3 -C ⁇ [4-(trifluoromethyl)phenyl] sulfonyl ) oxv)pyrrolidine- 1 -carboxylate
  • Step B ( ⁇ - (S- ⁇ Vl-Crer - uto ycaibonvnpyrrolidin-S-yl] l-fN- gr ⁇ -butyl-N-methylaminoMiazen- l-ium-l,2-diolate
  • Step A sodium l-(N-ferf-butyl- V r -i>ropylamino>diazen-l-ium-L2-diolate
  • Step B ⁇ -[l-(fe ⁇ butoxycarbonyDpipendin-4-yl] l- ⁇ -ferf-butyl-JV-propylamino iazen-l- ium-l,2-diolate
  • EXAMPLE 15 substituting ⁇ -[(3i?)-l-(ierf-butoxycarbonyI)pyiTolidin-3-yI] 1 -(N-tert-butyl-N- ethyIamino)diazen-l-ium-l,2-diolate (EXAMPLE 3) for ⁇ -[p -H ⁇ t-b toxycarbonyl) pyrrolidin-3-yl] 1 -(N-tert-butyl-iV-methylamino)diazen- 1 -ium- 1 ,2-diolate (EXAMPLE 1).
  • hydrochloride salt of the title compound was made by following the procedures described in EXAMPLE 15, substituting O 2 -[l-(/ert-butoxycarbonyl)piperidin-4-yl] l-(N-tert-butyl-N-ethylamino)diazen-l-ium-l s 2-diolate (EXAMPLE 6) for (f-[(3R)-Htert- butoxycarbonyl)pyrrolidin-3-yl] 1 -(N-teri-butyl-N-methylamino)diazen- 1 -ium- 1 ,2-diolate (EXAMPLE 1).
  • reaction mixture was stirred for 4 hours and quenched with saturated sodium carbonate (2 mL) and stirred for 30 minutes. It was diluted with diethyl ether (40 mL), and the combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo to afford a crude product. Chromatography over silica gel, eluting with hexanes/acetone, afforded the title compound as a yellow liquid.
  • Step A Q 2 - r (3 ?)-l-( ' 2-cvanopropan-2-yl)pyrrolidin-3-yl] l-(N-tgrt-butyl-N-methylamino)diazen- 1-ium- 1,2-diolate
  • reaction vial was sealed, and the reaction mixture was stirred at room temperature for 36 hours. It was diluted with diethyl ether (10 mL), washed with brine (2 x 2 mL), dried (magnesium sulfate), filtered and concentrated in vacuo to afford the title compound as a pale brown oil.
  • EXAMPLE 30 substituting methylmagnesium bromide for phenylmagnesium bromide in step B.
  • l H MR 500 MHz, CDC1 3 ) ⁇ 4.99 ⁇ .92 (m, IH), 3.16-3.10 (m, IH), 2.82 (s, 3H), 3.04-2.65 (m, 3H), 2.27-2.16 (m, IH), 2.10-2.04 (m, IH), 1.27 (s, 9H), 1.10 (s f 9H).
  • EXAMPLE 32 substituting 0 ⁇ piperidin-4-yl) 1 -(N-ter t-buty l-N-ethylamino)diazen- 1 -ium- 1 ,2- diolate (EXAMPLE 17) for 0 2 -[(3i?)-pyrrolidin-3-yl] l-(N-tert-butyl-N-ethylamino)diazen-l- ium-l,2-diolate (EXAMPLE 16).
  • the reaction mixture was heated with stirring to 80 °C for 3 hours. It was cooled down to room temperature, diluted with dichloromethane (10 mL), filtered through diatomaceous earth, and concentrated in vacuo to afford a crude product. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound.
  • Step A 3-(4-hydroxypiperidin-l -vDbenzonitnle
  • Step B O 2 - [ 1 -(3 -cvanophenyl piperidin-4-yll 1 -( N-fe ⁇ butyl-N-ethylamino iazen- 1 -ium-l 2- diolate
  • EXAMPLE 51 substituting C ⁇ -(piperidin-4-yl) l-(N-iert-butyl ⁇ N-ethylamino)diazen-l-ium-l ,2- diolate (EXAMPLE 17) for 0 2 -[(3i?)-pyrrolidin-3-yl] l-(N-mri-butyl-N-methylamino)diazen-l- ium-l,2-diolate (EXAMPLE 15). !
  • reaction was stirred at room temperature for 18 hours.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride solution (2 mL) and diluted with water (5 mL).
  • the reaction mixture was extracted with dichloromethane (3 x 20 mL), and the combined organics were washed with water, dried (magnesium sulfate), and concentrated in vacuo to afford the crude product. It was purified by mass-directed reversed- phase HPLC to afford the title compound.
  • Step A O azetidin-3-yl) 1 -(N-fert-butyl-N-methylamino diazen- 1 -ium- 1 ,2-diolate
  • EXAMPLE 15 substituting C ⁇ -[l-(im-butoxycarbonyl)azetidin-3-yl] l-(N- r -butyl-N- methylamino)diazen-l-ium-l J 2-diolate (EXAMPLE 13) for &-[(SR)- ⁇ - ⁇ tert- butoxycarbonyl)pyrrolidin-3 -yl] 1 -(N-tert-butyl-N-methylamino)diazen- 1 -ium- 1 ,2-diolate (EXAMPLE 3).
  • Step B Q 2 - ⁇ 1 -(phenylcarbonyl)azetidin-3 ⁇ yl1 1 -(N-fe t-butyl-N-methylamino)diazen- 1 -ium- 1 ,2- diolate
  • EXAMPLE 51 substituting 0 2 -[(3i-)-pyrrolidin-3-yi] l -(N- ⁇ ;t-butyl-N-ethylamino)diazen-l- ium-l,2-diolate (EXAMPLE 16) for 0 ⁇ -[(3 )-p)OTolidin-3-yl] l-(N ⁇ tert-butyl-N- methylamino)diazen-l -ium-1, 2-diolate (EXAMPLE 15).
  • Step A O 2 -ff3-3 ⁇ 4 -l-(fert-butylsulfinyl pyrrolidin-3-yl) l-fJV-fert-butyl-A ⁇ -methylamino iazen-l- ium-l,2-diolate
  • Step B Q 2 -[(3J3 ⁇ 4)-l-(terf-butylsulfonyl pyrrolidin-3-yl] l-(N-rgr ⁇ -butyl-jV-methylamino)diazen-l- ium-l,2-diolate
  • Step A (3 ⁇ -3-hydroxy- 1 -[4-(trifluoromethyl phenyl pyrrolidin-2-one
  • Step B (3iS f )-2-oxo-l-[4-(trifluoromethyl)phenyl pyrrolidin-3-yl 4-(trifluoromethyi)
  • Step C O 2 - ⁇ GR l-oxo- 1 - ⁇ 4-f trifluoromethvI)phenvnpyrrolidin-3-yl ⁇ 1 -(N-tert-butyl-N- methylamino diazen- 1 -ium- 1 ,2-diolate
  • EXAMPLE 32 substituting O 2 -[(3 ?)-pyrrolidin-3-yl] l-(N- ⁇ rr-butyl-N-methylamino)diazen-l- ium- 1,2-diolate (EXAMPLE 15) for ⁇ -[(S ⁇ -pyrroli in-S- l] l-(V-/ert-butyl-N- ethylamino)diazen- J -ium- 1,2-diolate. !
  • EXAMPLE 88 substituting O -[l-(5-cyanopyridin-2-yl)piperidin-4-yl] 1 -(jV-/ert ⁇ butyl-N- ethylamino)diazen-l -ium- 1 ,2-diolate (EXAMPLE 48) for ⁇ ? ⁇ [(3R)-1 -(2,2,2- trifluoroethyl)pyrrolidin-3-yl] 1 -(jV-teri-butyl-N-meth.ylaraino)diazen- 1 -ium- 1 ,2-diolate.
  • EXAMPLE 97 substituting 0 2 -[l-(2-methoxy-2-oxoethyl)piperidin-4-yl] l-(jV-tert-butyl-N- ethylamino)diazen-l-ium ,2-diolate (EXAMPLE 98) for 0*-[@R,5S)-5- (methoxycarbonyl)pyrroHdin-3 -yl] 1 -(iV-ieri-butyl-N-ethylamino)diazen- 1 -ium- 1 ,2-diolate (EXAMPLE 96).
  • Step B ⁇ -( ⁇ -il-g ⁇ -dioxo-l -thiazolidin-S-vnpiperidin ⁇ -yll ⁇ -(N-tert-bxxtv ⁇ -N- ethylamino)diazen-l -ium-1 ,2-diolate
  • Step A ⁇ - ⁇ (S gVl-iS-fetho vcarbo vn henvll yrrolidm-S-y l-(N-ferf-butyl-iV ⁇
  • EXAMPLE 108 substituting a 2 -[(3i?)-l-cyanopyrrolidin-3-yl] l-(N-ter -butyl-N-methylamino) diazen -ium-l,2-diolate (EXAMPLE 110) for O 2 -[(3i?)-l-(3-cyanophenyl)pyrrolidin-3-yI] 1-(N- ieri-but l- -methylammo)diazen-l-mm-l,2-diolate.
  • Step A f ⁇ )-N-(fert-butyl)-3-hydroxypyrrolidine-l-carboxamide
  • Step B Q 2 -
  • Compound evaluation consisted of a 3 day paradigm at a 3 mg/kg dose. On the first day, no compounds were administered during a 24 hour period of baseline data collection. Blood pressure and heart rate data were collected continuously for one minute periods at 10 minute intervals. On the days of compound administration half the animals received test article with the other half receiving the vehicle used for compound formulation. All test materials were administered by oral gavage in a volume of 1 mL/kg. Data are expressed either as raw values (mm Hg or beats per minute) or as the change from baseline (average value for about 12 hours in low activity period prior to dosing). Change is SBP (systolic blood pressure) and PP (pulse pressure) over time is shown below:
  • the exemplified compounds reduced blood pressure over the indicated time periods. Examples 1-6, 12, 14, 16, 3, 28, 30, 2-36, 8, 40-49, 51-56. 58-67, 70-73, 76, 80, 81, 88, 90, 92, 94, 100, 101, 103-108, 1 11-113, 1 15-1 19, 125, 126 were also tested in the canine telemetry protocol, and dropped blood pressure by at least 5 mm Hg over a 1-6 hour period of time.

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Abstract

La présente invention concerne un composé de structure : pouvant être employé dans le traitement de l'hypertension, de l'hypertension artérielle pulmonaire (HAP), de l'insuffisance cardiaque congestive, d'états pathologiques résultant d'un excès de rétention d'eau, de maladies cardio-vasculaires, du diabète, du stress oxydant, des dysfonctionnements endothéliaux, de la cirrhose, de la toxémie gravidique, de l'ostéoporose ou de la néphropathie.
PCT/US2011/057641 2010-10-29 2011-10-25 Dérivés hétérocycliques de diazéniumdiolate WO2012058203A1 (fr)

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BR112013009389A BR112013009389A2 (pt) 2010-10-29 2011-10-25 composto heterocíclico derivado de diazênio-diolato, e , composição farmacêutica
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JO3350B1 (ar) * 2011-03-07 2019-03-13 Merck Sharp & Dohme مشتقات حلقية غير متجانسة محتوية على مجموعات أمينو أولية ومركبات داي أزينيومديولات
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RU2013124814A (ru) 2014-12-10
EP2632255A4 (fr) 2014-07-23
AU2011320595A1 (en) 2013-06-06
KR20130143042A (ko) 2013-12-30
MX2013004739A (es) 2013-07-02
CN103347385A (zh) 2013-10-09
EP2632255B1 (fr) 2017-06-21
US9108920B2 (en) 2015-08-18
JP2013540817A (ja) 2013-11-07
BR112013009389A2 (pt) 2017-10-31
CA2814752A1 (fr) 2012-05-03

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